Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines.
OBJECTIVE
Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effect of YM155, a small-molecule inhibitor of survivin expression, on the sensitivity of human non-small cell lung cancer (NSCLC) cell lines to gamma-radiation.


METHODS
The radiosensitizing effect of YM155 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced DNA damage was evaluated on the basis of histone H2AX phosphorylation and foci formation.


RESULTS
YM155 induced down-regulation of survivin expression in NSCLC cells in a concentration- and time-dependent manner. A clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to gamma-radiation in vitro. The combination of YM155 and gamma-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone gamma-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and gamma-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone.


CONCLUSIONS
These results suggest that YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of YM155 is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression. Combined treatment with YM155 and radiation warrants investigation in clinical trials as a potential anticancer strategy.
Iwasa
Tsutomu
T
Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
Okamoto
Isamu
I
Suzuki
Minoru
M
Nakahara
Takahito
T
Yamanaka
Kentaro
K
Hatashita
Erina
E
Yamada
Yuki
Y
Fukuoka
Masahiro
M
Ono
Koji
K
Nakagawa
Kazuhiko
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D053148:Caspase 3 / Q000378:metabolism; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000528:radiation effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009285:Naphthoquinones / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015996:Survival Rate; D000077022:Survivin; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; C468783:H2AX protein, human; D006657:Histones; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D000077022:Survivin; D053148:Caspase 3; C523798:sepantronium